A Novel Molecular Target for Breast Cancer Prevention and Treatment
Abstract
We have investigated the mechanism by which retinoids induce apoptosis in breast cancer cells. Our results reveal a new apoptosis paradigm involving translocation of orphan receptor TR3 from the nucleus to the cytoplasm, where it targets mitochondria to induce cytochrome c release and apoptosis. The translocation of TR3 requires its unique heterodimerization with retinoid X receptor (RXRalpha). A putative nuclear export sequence (NES) in RXRalpha mediates nuclear export of TR3/RxRalpha heterodimer. The RXRalpha NES activities are regulated by RXR(X dimerization and ligand-binding. In studying how TR3 targets mitochondria, we have discovered that TR3 targets mitochondria through its interaction with Bcl-2. Bcl-2 acts as a mitochondrial receptor of TR3. It mediates the pro-apoptotic effects of TR3 by undergoing a conformational change upon TR3 binding. Such a conformational change converts Bcl-2 from a protector to killer. Together, our studies reveal a novel apoptotic pathway involving TR3, RXRalpha and Bcl-2 in breast cancer cells and our results provide various new strategies for developing agents against breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2004
- Accession Number
- ADA430517
Entities
People
- Xiao-kun Zhang
Organizations
- Sanford Burnham Prebys Medical Discovery Institute